Heparin-induced thrombocytopenia (HIT) is an iatrogenic complication associated with mild thrombocytopenia, but limb- and life-threatening thrombosis. The theme of this revised Program Project remains to understand the molecular mechanisms underlying HIT and to use that knowledge to develop new therapeutic approaches for its treatment. We believe that this is a timely proposal to combine several different, but highly interactive, efforts to advance our understanding and care of patients with HIT. There are four proposed Projects: Project 1: Cellular Events Underlying Thrombocytopenia and Thrombosis in HIT under Mortimer Poncz at the Children's Hospital of Philadelphia (CHOP) will examine the events that occur in vivo that lead to both the thrombocytopenia and prothrombotic state. Project 2: Pathogenic Antibodies in HIT under Douglas B. Cines at the University of Pennsylvania (UPENN) will better understand what distinguishes a pathogenic from a non-pathogenic anti-platelet factor 4 (PF4)/heparin Ab. Project 3: Immune Pathogenesis of HIT under Gowthami Arepally at Duke will study the physical characteristics of the PF4/heparin complex and the cellular basis of the pathogenic immune response in HIT. Project 4: Novel Therapeutics in HIT under Steven McKenzie at Thomas Jefferson University and Bruce Sachais at UPENN will study two novel strategies for early intervention to ameliorate this devastating disease on their own or in conjunction with present standard therapies. In addition to an administrative core, there are two cores involved. A Protein Core B under Lubica Rauova (CHOP) that will provide large quantities of human, mouse and specific mutant PF4s as well as large quantities of several HlT-like and control monoclonal Abs. This Core will also isolate batched large-scale HIT IgGs as well as individual HIT IgG samples from plasma isolated and processed by the Clinical Sample Core C under Dr. Cines. Core C will be responsible for identifying high likelihood of HIT patients at all three major adult programs, consent the individuals and obtain plasma from them as well as record their clinical and serological data. We believe that the proposed Projects are highly interactive. Advances and technologies developed within each will have great value to other Projects. Moreover the Cores will provide unique materials in large amounts and to high standards that will allow rapid scientific progress and easy crosstalk between projects. At the end of the 5 years of support, we believe that important fundamental and clinically useful information will have been generated for a disease that remains highly clinically relevant.